title: Vascular disrupting agent DMXAA enhances the antitumor effects generated by therapeutic HPV DNA vaccines.
abstract: Antigen-specific immunotherapy using DNA vaccines has emerged as an attractive approach for the control of tumors. Another novel cancer therapy involves the employment of the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA). In the current study, we aimed to test the combination of DMXAA treatment with human papillomavirus type 16 (HPV-16) E7 DNA vaccination to enhance the antitumor effects and E7-specific CD8+ T cell immune responses in treated mice. We determined that treatment with DMXAA generates significant therapeutic effects against TC-1 tumors but does not enhance the antigen-specific immune responses in tumor bearing mice. We then found that combination of DMXAA treatment with E7 DNA vaccination generates potent antitumor effects and E7-specific CD8+ T cell immune responses in the splenocytes of tumor bearing mice. Furthermore, the DMXAA-mediated enhancement or suppression of E7-specific CD8+ T cell immune responses generated by CRT/E7 DNA vaccination was found to be dependent on the time of administration of DMXAA and was also applicable to other antigen-specific vaccines. In addition, we determined that inducible nitric oxide synthase (iNOS) plays a role in the immune suppression caused by DMXAA administration before DNA vaccination. Our study has significant implications for future clinical translation.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.forename: Archana
authors.initials: A
authors.lastname: Monie
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Pang
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D044004:Xanthones / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA; D044004:Xanthones; C066668:vadimezan